Beta-hydroxy bis heterocyclic aryl derivatives of acrylonitrile



United States Patent 3,337,566 BETA-HYDRUXY BlS HETEROCYKILIC ARYLDERHVATIVES @F AQRYLQNITRILE Gordon Northrop Walker, Morristowu, WilliamLaszlo Bencze, New Providence, and John Benjamin Ziegler, Summit, N..l.,assignors to Ciba Corporation, New York, N.Y., a corporation of DelawareNo Drawing. Filed Apr, 28, 1966, Ser. No. 545,875 9 Claims. (Cl.269-294.?)

This is a continuation-in-part of application Ser. No. 466,826, filedJune 24, 1965.

The present invention concerns and has for its object the provision offi-hydroxy-acrylic acid derivatives of the formula in which the radicalsAr, and Ar stand for a monoor bicyclic heterocy-clic aryl radical, theenol ethers and esters thereof and the acid esters, amides and thenitrile, as well as salts of these compounds, and methods for theirpreparation.

A heterocyclic aryl radical is, for example, an aza-, oxaand/ orthiacyclic aryl radical, preferably a monoazacyclic aryl radical, suchas a 2-, 4- or especially 3- pyridyl radical, but also, for example, a2- or 3-pyrryl, 3- or 4-pyrazyl, 2-, 4- or S-imidazolyl, 2- or 3-furyl,2- or 3-thienyl, 2-, 4- or 5-0xazolyl or thiazolyl, 3-, 4- or 5-isoxazolyl or isothiazolyl, 3- or 4-pyridazinyl, 2-, 4- or 5- pyrimidyl,Z-pyrazinyl, 2- or 3-indolyl, 1- or 3-isoindolyl, 2-, 3-, 4- orS-quinolyl or 1-, 3-, 4- or 7-isoquinoly1 radical.

These radicals Ar, and Ar which may be identical or different, areunsubstituted or contain one or more than one of the same or ofdifferent substituents, such as lower alkyl, e.g. methyl, ethyl, nori-propyl, n-, i-, sec.- or tert-butyl, lower alkoxy, e.g. methoxy,ethoxy, nor i-propoxy or n-butoxy, lower alkylmercapto, e.g. methylorethylmercapto, halogen, e.g. fluoro, chloro or bromo, trifluoromethyl,nitro or amino, such as di-lower alkylamino, e.g. dimethylamino ordiethylamino.

An enolether is, for example, such derived from an aliphatic oraraliphatic alcohol, such as a lower alkanol or aralkanol, e.g.methanol, ethanol, nor i-propanol, nbutanol or benzyl alcohol. An enolester is preferably that of a carboxylic or sulfonic acid, such as alower alkanoic or lower alkane or benzene sulfonic acid, e.g. formic,acetic, propionic, butyric, pivalic, methane sulfonic, ethane sulfonicor p-toluene sulfonic acid.

An ester of the present B-hydroXy-acrylic acids is preferably suchderived from the above-mentioned aliphatic or araliphatic alcohols. Acorresponding amide may be the unsubstituted amide or a monoor di-loweralkylamide in which lower alkyl has the meaning given above.

The compounds of the present invention have valuable pharmacologicalproperties. For example, they interfere with the carbohydrate metabolismand cause a fall in the sugar content of the blood. This can bedemonstrated, for example, in glucose primed intact or adrenalectomizedrats over an oral dosage range between about 1- to 200 mg/kg. They are,therefore, useful as hypoglycemic agents, preferably for oraladministration. They are also useful starting materials or intermediatesin the manufacture of other valuable compounds, especially medicines.

Particularly useful are the compounds of the formula in which theradicals Ar and Ar, stand for 2-, 3- or 4- pyridyl, 2- or 3-furyl, 2- or3-thienyl, 2-, 3- or 4-quino1yl,

l-, 3- or 4-isoquinolyl, or one of these radicals containing one or twosubstituents selected from lower alkyl, lower alkoxy and halogen, R forcyano, carbamyl, lower alkylcarbamyl, N,N-di-lower alkylcarbamyl andcarbo-lower alkoxy and R for hydrogen, lower alkyl or lower alkanoyl.

Compounds that are specially valuable are those of the formulaA15C=C-Al'a in which Ar,- and Ar stand for 2-, 4- or especially3-pyridyl or (lower alkyl)-pyridyl and R for carbamyl or cyano.

Above all, the present invention concerns compounds having the formulaeR3 R3 N 1 on (IJONHQ I and CH A11-C=C-Arz with a base or (d) Reacting acompound of the formula 3|; An-CO-CI-I-Al'z or an enolether or esterthereof, in which X stands for a halogen atom, with a cyanide or areactive functional derivative of formic acid or (e) Reacting a compoundof the formula or a reactive metal derivative thereof, with a halocyanor an aliphatic or araliphatic haloformiate or halooxalate anddecarbonylating any :glyoxalate obtained and, if desired, converting afree compound obtained into an enol ether or ester, an acid ester,amide, nitrile or salt thereof or converting a corresponding functionalderivative or salt thereof into the free compound or into another ofsaid derivatives and/or separating a mixture of isomers into the singleisomers.

An ester of the heterocyclic acid Ar -CODE is preferably that of analiphatic or araliphatic alcohol, for example of those mentioned above,a halide is preferably the chloride or bromide and an anhydride a pureor mixed anhydride. An ester of the acid Ar --CH COOH is, for example,also that of the above-mentioned aliphatic or araliphatic alcohols,whereas its amide preferably is derived of a secondary amine, such as adi-lower alkylamine. Reaction a) is preferably performed with thecorresponding nitrile and in the presence of a condensing agent, forexample an alkali metal, e.g. lithium, sodium or potassium, or analcoholate thereof, advantageously a lower alkanolate, e.g. methanolate,ethanolate, nor ipropanolate, nor tert. butanolate, or an amide orhydride thereof or any other condensing agent useful in Claisencondensations. The acid halide is preferably reacted with the metalderivative, whereas the acid anhydride advantageously is reacted in thepresence of a Lewis acid, e.g. boron trifluoride.

The esters or amides of the starting material mentioned under (b) are,for example, those mentioned for the final products. An amino group Rtherein may be unsubstituted or substituted, preferably disubstituted,and represents, for example di-lower alkylamino or advantageously loweralkyleneimino, aza-, oxaor thia-alkyleneimino, such as, dimethylamino,diethylamino, di-n-propylamino or di-nbutylamino; pyrrolidino,piperidino, N-lower alkyl-piperazino, morpholino or thiamorpholino. Ahalogen atom R advantageously stands for bromine. The hydrolysis of saidenamines is preferably carried out in an acidic medium, such as anaqueous acid, for example a mineral acid, such as a hydrohalic acid,e.g. hydrochloric, hydrobromic or hydriodic acid, perchloric, sulfuricor phosphoric acid, a sulfonic acid, such as a lower alkane or benzenesulfonic acid, e.g. methane, ethane or p-toluene sulfonic acid, or withthe use of nitrous acid. The hydrolysis of the corresponding halocompound is preferably carried out in an alkaline medium, for example,an aqueous alkali metal hydroxide or carbonate, e.g. sodium or potassiumhydroxide or carbonate, an alkali metal alkanolate, e.g. that mentionedabove or any other agent suitable for the hydrolysis of unsaturatedhalogen compounds.

The compounds mentioned under (c) can be isomerized into thecorresponding fi-hydroxy-acrylonitriles by the action of alkalineagents, e.g. those mentioned hereinbefore, advantageously with an alkalimetal lower alkanolate.

An enolether or ester of the starting material mentioned under (d) is,for example, such mentioned for the final products. A halogen atomtherein stands preferably for chlorine or advantageously bromine. Thesecompounds are reacted with a cyanide, preferably an alkali metal orammonium cyanide, or a reactive functional derivative of formic acid,such as an ester or orthoester thereof, derived preferably of analiphatic or araliphatic alcohol, or a formamide.

A reactive metal derivative of the starting material mentioned under (e)is, for example, an alkali metal, e.g. sodium or potassium, derivativethereof. The halocyan, haloformiate or halooxalate used as reactant isadvantageously the chloro or bromo compound. The decarbonylation of aglyoxalate obtained may be performed by pyrolysis, advantageously invacuo.

Any free compound obtained may be converted into one of said enol and/or carboxylic acid derivatives thereof according to methods known perse. For example, any free enol may be etherified, for example, with areactive functional derivative of an aliphatic or araliphatic alcohol,such as its ester with a hydrohalic or sulfuric acid, or esterified witha reactive functional derivative of a corresponding acid, such as ananhydride or halide thereof. From a free acid a salt, an ester or amidemay be prepared according to known methods, in order to obtain thederivatives mentioned in the beginning.

Alternatively any derivative obtained may be converted into the freecompounds, for example, esters, ethers, amides or nitriles byhydrolysis, or into another derivative, for example, nitriles intoamides by partial hydrolysis, esters into other esters bytransesterification, substituted amides by reaction of the unsubstitutedamides with a reactive ester of an alcohol, preferably a hydrohalic acidester of a lower alkanol, acids or acid derivatives into amides, forexample, by reaction of esters, anhydrides or acid halides with ammoniaor amines. Also in the heterocyclic moiety a substituent, such as alower alkyl group, may be added to a nitrogen atom present, for example,as shown for the substituted amides above.

The final products are obtained in the free form or in the form of theirammonium or metal salts (derived either from the acid or the enol), oracid addition salts respectively (derived from any basic heterocycle),depending on the conditions under which the process is carried out; thesalts are also included in the present invention. Salts that areobtained can be converted into the free compounds for example, byreacting them with an acidic or basic agent respectively, such as amineral acid or strong organic acid, e.g. those mentioned above, or ametal hydroxide, e.g. sodium, potassium or calcium hydroxide, an alkalimetal carbonate, e.g. sodium or potassium carbonate or hydrogencarbonate, ammonia or a hydroxy-l ion exchange preparation.

A resulting salt may also be converted into another salt, for example byits treatment with a suitable ion exchange preparation. Furthermore, asalt may be converted into another salt which is less soluble in theparticular solvent used, for example by reacting it with an acid or baserespectively, or a soluble salt thereof.

A free acid is converted into its salts, especially its ammonium, alkalior alkaline earth metal salts, e.g. sodium, potassium or calcium salts,by reaction with a corresponding hydroxide, carbonate, hydrogencarbonate or cation exchange preparation.

A free base is converted into a salt thereof, by its treatment with anacid or an anion exchange preparation. Preferred salts are those oftherapeutically useful acids, such as inorganic acids, e.g.hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, ororganic acids, such as carboxylic or sulfonic acids, e.g. acetic,propionic, glycolic, malonic, suecinic, maleic, hydroxymaleic, fumaric,malic, tartaric, citric, glucuronic, benzoic, salicylic, 4-aminosalicyclic, 2-acetoxybenzoic, pamoic, nicotinic, isonicotinic,methane sulfonic, ethane sulfonic, ethane 1,2- disulfonic,Z-hydroxyethane sulfonic, benzene sulfonic, toluene sulfonic ornaphthalene 2-sulfonic acid, methionine, lysine, tryptophan or arginine.Other acid addition salts are useful as intermediates for thepreparation of the pure parent compounds or in the manufacture of othersalts, as well as for identification or characterization purposes.Addition salts primarily used for the latter are, for example, thosewith certain inorganic acids, e.g. perchloric, phosphotungstic,phosphomolybdic, chloroplatinic or Reinecke acid or with acidic organicnitro compounds, e.g. picric, picrolonic or fiavianic acid. The basesare converted into salts, the salts are separated and the basesliberated from the salts. In view of the close relationship between thefree compounds and the compounds in the form of their salts, whenever afree compound is referred to in this contex, a corresponding salt isalso intended, provided such is possible and useful.

Resulting mixtures of isomeric compounds may be separated into singleisomers based, for example, on physico-chemical difierences, such asdilferent solubilities or different boiling points. Thus, mixtures ofisomers of racemates may be separated by fractional crystallization orfractional distillation, if necessary, by using a derivative thereof,e.g. a salt. Racemic products can likewise be resolved into the opticalantipodes, for example, by reaction with optically active acids,separation of the diastereomeric salts and liberation of the bases fromthe sa ts.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/ or inert atmospheres, at loW temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage thereof is used asstarting material and any remaining step or steps is/are carried out orthe process is discontinued at any stage thereof or in which thestarting materials are formed in situ or the reactants are used in theform of their salts. The present reactions are preferably performed withstarting materials that give rise to the preferred compounds mentionedabove.

The starting materials used are known or, if new, may be preparedaccording to known procedures. The enamines shown under (b) may beobtained by reaction of a compound having the formula Am AIy-(J CH-At'zin which Am stands for a tertiary amino group, preferably pyrrolidino,with bromocyan or a lower alkyl bromoformiate [see, for example, J.Amer. Chem. Soc. 81, 5400 (1959)]. Alternatively such starting materialsmay be prepared by reacting a Grignard derivative of the acid Ar -CHCOOH (Ivanov reagent) with the nitrile Ar CN. The correspondinghalo-compounds may be prepared by reacting a trihalide Ar -C(Hal) withan ester, amide or the nitrile of the acid Ar CH --COOH.

The compounds shown under (c) can be prepared by formylation of thoseshown under (e), for example with the use of a lower alkyl formiate ororthoformiate under Claisen conditions, and reacting the resultinghydroxymethylene compound with hydroxylamine in order to obtain thedesired isoxazoles.

The compounds shown under (d) can be prepared by halogenation of thecorresponding unsubstituted compounds, either with a halogen itself orwith the use of a halogenating agent, such as an N-halogenimide, e.g. N-bromo-succinimide.

The compounds of this invention are useful in the form of compositions,especially for enteral, e.g. oral use, which contain a pharmacologicallyefiective amount of the active compound of this invention in admixturewith a pharmaceutically acceptable organic or inorganic, solid or liquidcarrier. For making up the latter, there are employed the usual carriermaterials suitable for the manufacture of pharmaceutical compositions,such as water, gelatine, sugars, e.g. lactose, sucrose or glucose,starches, e.g. corn starch, wheat starch or rice starch, stearic acid orsalts thereof, e.g. magnesium or calcium stearate, talc, vegetable oils,ethanol, stearyl alcohol, benzyl alcohol, gums, acacia, tragacanth,polyalkylene glycols, propylene glycol or any other suitable excipientor mixtures thereof. The compositions may be in solid form, e.g.capsules, tablets, dragees or suppositories, or in liquid form, e.g.solutions, suspensions or emulsions. If desired, they may containauxiliary substances, such as preserving, stabilizing, wetting,emulsifying, coloring or flavoring agents, salts for varying the osmoticpressure and/ or buffers. The above preparations are prepared accordingto the standard methods used for the manufacture of pharmaceuticallyacceptable compositions, which, if desired, may also contain, incombination, other physiologically useful substances.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade and all parts are parts by weight.

Example 1 Dry sodium methoxide (prepared by dissolving 7.7 g. sodium inmethanol and the evaporation of excess methanol on a steam cone invacuo) is suspended in 500 ml. diethyl ether and 39.1 g.3-pyridyl-acetonitrile and 50 g. ethyl nicotinate are added. Thesuspension is stirred and then allowed to stand overnight. Theorange-brown sodium salt formed is collected, washed with ether, anddissolved in water. The maroon-colored, clarified aqueous solution isneutralized to a pH of about 7 by addition of dilute hydrochloric acid.The yellow crystals formed are collected, washed with water andair-dried. The so- 6 obtained a,,8 bis(3-pyridyl)-fi-hydroxy-acrylonit1ile of the formula is recrystallizedfrom methanol and melts at 251252 (dec.).

Its infrared spectrum (Nujol) shows peaks at 4.59 and 6.35, and theultraviolet spectrum (Methanol) shows a kmax, at 238, 274 and 336 m14,180, 5880 and 14,010 respectively. In 0.1 N potassium hydroxide theultraviolet spectrum shows a A at 222, 272'and 330 m e=13,190, 8590 and12,980 respectively, with infiection at 240 m 5:9670.

Example 2 28.2 g. sodium methoxide are dissolved in 140 ml. absoluteethanol and to the rapidly stirred solution the mixture of 75.6 g. ethylnicotinate and 47.6 g. S-pyridylacetonitrile is added rapidly. Theyellowish-brown mixture obtained is refluxed for 2.5 hours and allowedto cool to room temperature for 24 hours. Hereupon 500 m1. ice-water areadded and the solution is filtered to remove a trace of blue-grayflocks. The filtrate is neutralized to a pH of about 6 to 7 with 30 ml.glacial acetic acid and the thick mush of yellow crystals is kept atroom temperature overnight. It is filtered, the crystals are washedthoroughly with ice water and dried in vacuo at 70. There is obtainedthe a,fl-bis-(3-pyridyl)-,8-hydroxyacrylonitrile as a yellowmicrocrystalline powder melting at 252253 with decomposition; it isidentical with that obtained according to Example 1.

10.0 g. thereof are converted into the corresponding amide by treatmentwith ml. concentrated sulfuric acid containing 10 ml. fuming sulfuricacid, for about 3 hours at room temperature. The mixture is poured overice, the crystalline material collected, washed with dilute ammonia,water and methanol and recrystallized from ethanol.

Example 3 In the analogous manner shown in the previous examples, butusing instead of 3-pyridyl-acetonitrile an equivalent amount of ethyl 2-or 3-pyridyl-acetate, the ethyl a-(Z- or 3-pyridyl)-,8-hydroxy-,8(3-pyridyl)-acrylate is obtained. Accordingly, the nitrile, amide andethylester of the following acids can be prepared:

1.92 g. sodium are added to 27 ml. absolute ethanol which is thenrefluxed for 1 hour. Hereupon the solution of 7.7 g.4-pyridyl-acetonitrile in 13.59 g. ethyl isonicotinate is added slowlyand the stirred mixture is refluxed for 4 hours. It is poured intowater, the whole is extracted with diethyl ether, the aqueous layeracidified with acetic acid and the precipitate formed filtered ofi? anddried. It is recrystallized from dimethyl formamide-ethanol and washedwith hot ethanol to yield the a,[i-bis-(4-pyridyl)-,B-hydroxy-acylonitrile of the formula OH oN melting at 312-314(decomp).

o:o o melting after another recrystallization from n-butanol at 255-258.

Example 6 In the analogous manner described hereinbefore, the followingcompounds can be prepared from equivalent amounts of the correspondingstarting material:

u- 3-pyridyl) -B-hydroxy-B- (2-thienyl) -acrylonitrile, a- (3-pyridyl-fi-hydroxy-,B- 3-pyrazolyl) -acrylonitrile, a- 3-pyridyl)-5-hydroxy-fi- (5 -methyl-3-pyrazolyl acrylonitrile, oz- (4-pyridyl)-fl-hydroxy-fl- (4-thiazolyl) -acrylonitrile and 01- (3-pyridyl)-,8-hydroXy-fl- (2-methyl-4-thiazolyl acrylonitrile.

Example 7 3.8 g. sodium are reacted with an excess of methanol and thesolution obtained is evaporated in vacuo. To the residue the mixture of17.7 g. 3-pyridyl-acetonitrile and 25.8 g. ethyl 2-thiophenecarboxylateis added while stirring during /2 hour. Hereupon the mixture is allowedto stand overnight. It is then triturated with diethyl ether anddissolved in about 200 ml. water. The red solution is washed withdiethyl ether and neutralized with 18% hydrochloric acid. The yellowprecipitated formed is filtered off, washed with water and dried toyield the a-(lpyridyl)-}3-hydroxy-B-(Z-thienyl)-acrylonitrile of theformula m llyon 3N :c s melting at 23 l-232 after recrystallization fromethanol. Example 8 30.0 g. a,fi-bis-(3-pyridyl)-fl-hydroxy-acrylonitrileare dissolved in 200 ml. warm methanolic hydrochloric acid and thesolution is cooled in an ice bath for about half an hour wherebycrystallization occurs. The precipitate formed is filtered off and airdried to yield the oc,/3-biS-(3 pyridyl)-;8-hydroxy-acry1onitrilemonohydrochloride melting at 265.

Example 9 1000 tablets each containing 0.5 g. of the active ingredient.

Material: G. a,fl-bis-(3-pyridyl)-5-hydroxy-acrylonitrile 500.0

Anydrous ethanol, q.s. Purified Water, q.s.

Procedure: All powders with the exception of the silica and starch arepassed through a screen having an opening 8 of 1.2 mm. and mixed well.From the starch and 65 ml. Water a paste is formed which is used togranulate the powders together with the ethanol. The wet granulate ispassed through a screen with 2 mm. opening and dried at 43. The drygranulate is broken in a hammer mill, passed through a screen with 1.2mm. opening and compressed into tablets each weighing 0.65 g. usingstandard concave punches.

What is claimed is: 1. A member selected from the group consisting of acompound having the formula RzO CN AI3-G=CAl'4 in which each of theradicals Ar and An; stands for a member selected from the groupconsisting of Z-pyridyl, 3-pyridyl, 4-pyridyl, 2furyl, 3-furyl,2-thienyl, 3-thienyl, Z-quinolyl, 3-quinolyl, 4-quinolyl, l-isoquinolyl,3-isoquinolyl, 4-isoquinolyl and one of these radicals containing atmost two substituents selected from the group consisting of lower alkyl,lower alkoxy and halogeno, and R for a member selected from the groupconsisting of hydrogen, lower alkyl and lower alkanoyl, the alkali metalsalts and therapeutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 and having the formula 011 ON Ar 3-(JAr B in which each of Ar and Ar stands for a member selected from thegroup consisting of 2-pyridyl, 4-pyridyl, (lower alkyl)-2-pyridyl and(lower alkyl)-4-pyridyl, the alkali metal and therapeutically acceptableacid addition salts thereof.

3. A compound as claimed in claim 1 and having the formula OH 0N Af5C lC-Af5 in which Ar and Ar stand for a member selected from the groupconsisting of 3-pyridyl and (lower alkyl)-3- pyridyl, the alkali metaland therapeutically acceptable acid addition salts thereof.

4. A compound as claimed in claim 1 and having the 0H ON formula inwhich R stands for a member selected from the group consisting ofhydrogen and methyl, the alkali metal and therapeutically acceptableacid addition salts thereof.

5. A compound as claimed in claim 1 and being the u,fl-bis- 3-pyridyl)-B-hydroxy-acrylonitrile.

6. A compound as claimed in claim 1 and being thea,,8-bis-(3-pyridyl)-/3-hydroxy-acrylonitrile hydrochloride.

7. A compound as claimed in claim 1 and being the oc,fl-biS 4-pyridyl)-B-hydroxy-acrylonitrile.

8. A compound as claimed in claim 1 and being the OL- 3 -pyridyl-fi-hydroxy-/8- 2-furyl) -acrylonitrile.

9. A compound as claimed in claim 1 and being the oc- (3 -pyridyl-/3-hydroxy-B-(2-thienyl) -acrylonitrile.

References Cited Burger: Medicinal Chemistry, 2nd ed., Interscience,page 78.

WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

A. L. ROTHMAN, Assistant Examiner.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THEFORMULA